Abstract
Runs of homozygosity (ROH) represents extended length of homozygotes on a long genomic distance. In oncology, it is known as loss of heterozygosity (LOH) if identified exclusively in cancer cell rather than in matched control cell. Studies have identified several genomic regions which show consistent ROH in different kinds of carcinoma. To query whether this consistency can be observed on broader spectrum, both in more cancer types and in wider genomic regions, we investigated ROH patterns in the National Cancer Institute 60 cancer cell line panel (NCI-60) and HapMap Caucasian healthy trio families. Using results from Affymetrix 500 K SNP arrays, we report a genome wide significant association of ROH regions between the NCI-60 and HapMap samples, with much a higher level of ROH (11 fold) in the cancer cell lines. Analysis shows that more severe ROH found in cancer cells appears to be the extension of existing ROH in healthy state. In the HapMap trios, the adult subgroup had a slightly but significantly higher level (1.02 fold) of ROH than did the young subgroup. For several ROH regions we observed the co-occurrence of fragile sites (FRAs). However, FRA on the genome wide level does not show a clear relationship with ROH regions.
Highlights
In diploid organisms, SNPs are categorized into heterozygotes and homozygotes according to the difference/identity between paternal and maternal alleles
The same chromosome regions with increased ROH frequency (ROHF) in the National Cancer Institute (NCI)-60 were found to occur in the HapMap non-cancerous samples but with lower ROHF (Figure 1)
Significant correlations between the NCI-60 and HapMap ROHF were found on all chromosomes before and after adjustment for SNP density and hemizygous deletion frequency (HDF) (Table 1, 12th column)
Summary
SNPs are categorized into heterozygotes and homozygotes according to the difference/identity between paternal and maternal alleles. LOH may cause tumor suppressor gene loss of function, which is associated with oncogenesis [2]. Genomic regions affected by LOH often exhibit an extended length of homozygous SNPs, which forms regions with low diversity between two copies of DNA. Studies in E. coli [3], Trypanosoma brucei [4] and mouse [5] show the importance of extended sequence similarity/diversity in promoting/preventing homologous recombination. This recombination, if happened during mitotic process, maybe related to subsequent LOH [6] and affects genome stability [7,8]. A study by Assie, G et al [11] investigated breast, prostate, head and neck carcinomas and found 16 common loci that have significantly increased germline homozygosity frequency
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